Project Summary Drug metabolism, programmed cell death, DNA biosynthesis and repair, respiration, and photosynthesis are familiar biological processes of critical importance to human health that rely on protein-mediated electron-transfer (ET) reaction mechanisms for their function. As such, ET pathways lie at the core of life, and the malfunction of ET pathways is an underlying cause of diseases, notably diseases triggered by oxidative stress and malfunction of the mitochondrial machinery. Since ET is a process common to all forms of life, a molecular-level understanding of ET pathways in pathogenic organisms may be exploited for therapeutic advantage as well. The long-term objective of this research is to understand, at the molecular, meso, and macro scales, how biological structure and dynamics influence crucial ET reactions. Theoretical findings from this laboratory over two decades have discovered how protein structure and dynamics can modulate ET reaction mechanisms and on the nanometer length scales, and the laboratory has established widely used methods to predict the corresponding ET rates. In the last grant period we turned our focus to charge-transport systems that function on much longer length scales, where grand challenge questions are emerging regarding ET mechanism and function on the multiple nanometer to the centimeter length scales. The research proposed here focuses on: (1) the charge hopping transport on the multiple nanometer scale associated with redox-based signaling and charge hopping that relieves oxidative stress; (2) charge transport on the micrometer scale, where the anomalous kinetic signatures discovered in multi-heme extracellular bacterial appendages will be examined; (3) transport in cable bacteria on the centimeter scale, where multi-cellular bacterial assemblies with a shared outer membrane extract energy by bridging physically between reducing and oxidizing environments, exploiting a common ET conduit that enables collaboration and a rudimentary demonstration of the benefits of multi-cellularity. A hallmark of this research program has been its close collaboration between theory and cutting-edge experiment, and this core approach will continue with intensive collaborations involving Aarhus University (Denmark), the University of Antwerp (Belgium), the University of California- Irvine (USA), and Caltech (USA).